Background
The coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2, is a global public health emergency. Data on the effect of coronavirus disease 2019 in pregnancy are limited to small case series.
Objective
To evaluate the clinical characteristics and outcomes in pregnancy and the vertical transmission potential of severe acute respiratory syndrome coronavirus 2 infection.
Study Design
Clinical records were retrospectively reviewed for 116 pregnant women with coronavirus disease 2019 pneumonia from 25 hospitals in China between January 20, 2020, and March 24, 2020. Evidence of vertical transmission was assessed by testing for severe acute respiratory syndrome coronavirus 2 in amniotic fluid, cord blood, and neonatal pharyngeal swab samples.
Results
The median gestational age on admission was 38 +0 (interquartile range, 36 +0 –39 +1 ) weeks. The most common symptoms were fever (50.9%, 59/116) and cough (28.4%, 33/116); 23.3% (27/116) patients presented without symptoms. Abnormal radiologic findings were found in 96.3% (104/108) of cases. Of the 116 cases, there were 8 cases (6.9%) of severe pneumonia but no maternal deaths. One of 8 patients who presented in the first trimester and early second trimester had a missed spontaneous abortion. Of 99 patients, 21 (21.2%) who delivered had preterm birth, including 6 with preterm premature rupture of membranes. The rate of spontaneous preterm birth before 37 weeks’ gestation was 6.1% (6/99). One case of severe neonatal asphyxia resulted in neonatal death. Furthermore, 86 of the 100 neonates tested for severe acute respiratory syndrome coronavirus 2 had negative results; of these, paired amniotic fluid and cord blood samples from 10 neonates used to test for severe acute respiratory syndrome coronavirus 2 had negative results.
Conclusion
Severe acute respiratory syndrome coronavirus 2 infection during pregnancy is not associated with an increased risk of spontaneous abortion and spontaneous preterm birth. There is no evidence of vertical transmission of severe acute respiratory syndrome coronavirus 2 infection when the infection manifests during the third trimester of pregnancy.
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The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health emergency. Since the first case of COVID-19 pneumonia was reported in Wuhan, Hubei Province, China, in December 2019, the infection has spread rapidly to the rest of China and beyond. Coronaviruses are enveloped, nonsegmented, positive-sense RNA viruses belonging to the family Coronaviridae, order Nidovirales. The epidemics caused by 2 β-coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), have caused more than 10,000 cumulative cases in the past 2 decades, with mortality rates of 10% for SARS-CoV and 37% for MERS-CoV. Severe acute respiratory syndrome coronavirus 2 belongs to the same β-coronavirus subgroup, and it has genome similarity of about 80% and 50% with SARS-CoV and MERS-CoV, respectively. The latest report from the World Health Organization (WHO) on March 3, 2020, estimated the global mortality rate of COVID-19 to be 3.4%, although recent reports that have used appropriate adjustment for the case ascertainment rate and time lag between symptoms onset and death suggest the mortality rate to be lower at 1.4%.
Why was this study conducted?
- •
To report maternal and neonatal outcome of coronavirus disease 2019 (COVID-19) in pregnancy of 116 patients.
Key findings
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There were 8 cases (6.9%, 8/116) of severe pneumonia but no maternal deaths.
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One of 8 patients (12.5%, 1/8) who presented in the first trimester and early second trimester had a missed spontaneous abortion.
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The rate of spontaneous preterm birth before 37 weeks’ gestation was 6.1% (6/99).
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Eighty-six of 100 neonates tested for severe acute respiratory syndrome coronavirus (SARS-CoV-2), had negative results.
What does this add to what is known?
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SARS-CoV-2 infection during pregnancy is not associated with an increased risk of spontaneous abortion and spontaneous preterm birth.
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There is no evidence of vertical transmission of SARS-CoV-2 infection when the infection manifests during the third trimester of pregnancy.
Pregnant women are especially susceptible to respiratory pathogens and severe pneumonia, because of the physiological changes in the immune and cardiopulmonary systems (eg, diaphragm elevation, increased oxygen consumption, and edema of the respiratory tract mucosa), which can render them intolerant to hypoxia. The 1918 influenza pandemic caused a mortality rate of 2.6% in the overall population, but 37% among pregnant women. In 2009, pregnant women were reported to be at an increased risk for complications from the pandemic H1N1 2009 influenza virus infection, with a higher estimated rate of hospital admission than in the general population. In 2003, it was reported that approximately 50% of pregnant women who received a diagnosis for SARS-CoV were admitted to the intensive care unit (ICU), around 33% of pregnant women with SARS-CoV required mechanical ventilation, and the mortality rate was as high as 25% for these women.
To date, data on the effect of COVID-19 in pregnancy are limited to small case series. This multicenter study aimed to evaluate the clinical characteristics and outcomes of 116 pregnant women with COVID-19 pneumonia and the vertical transmission potential of SARS-CoV-2 infection.
Materials and Methods
Study design and participants
This study was reviewed and approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (reference 2020004) and Renmin Hospital of Wuhan University (reference WDRY2020-K015, WDRY2020-K016). For the collection of clinical data, verbal consent from pregnant women was obtained, and written informed consent was waived considering the urgent need to collect data. Written informed consent was obtained from pregnant women who agreed to the testing of biological samples and neonatal pharyngeal swab samples. Data were analyzed and interpreted by the authors. All the authors reviewed the manuscript and vouched for the accuracy and completeness of the data and for the adherence of the study to the protocol. The funding agencies did not participate in the study design, data collection, data analysis, or writing of the report.
Data collection
This was an expanded series from 4 previous small case series. , We obtained the medical records and compiled clinical and outcome data for consecutive pregnant women with COVID-19 pneumonia from 25 hospitals ( Supplemental Material ) within and outside of Hubei Province between January 20, 2020, and March 24, 2020. COVID-19 was diagnosed on the basis of the New Coronavirus Pneumonia Prevention and Control Program published by the National Health Commission of China. A laboratory-confirmed case of COVID-19 was defined as a positive result by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay of maternal pharyngeal swab specimens. At the peak of the COVID-19 outbreak within Hubei Province, China, cases with relevant symptoms, marked epidemiologic history, and typical chest computed tomography (CT) findings were clinically diagnosed as COVID-19 pneumonia, whereas the viral nucleic acid test was reported to have a false-negative rate of 30%.
Complete epidemiologic history, clinical symptoms or signs, laboratory and radiologic findings, treatment measures, and outcome data were extracted from electronic medical records by a team of experienced clinicians and curated with customized data collection form. All laboratory testing and radiologic assessments, including chest CT, were performed according to the clinical care needs of the patient. Laboratory assessments consisted of complete blood cell count, liver and renal function, electrolytes, C-reactive protein, and coagulation testing. We determined the presence of a radiologic abnormality based on the documentation or description in medical charts. The date of onset of disease was defined as the day when the symptoms were noticed. The intervals from onset of disease to hospital admission and delivery were recorded. Data on pregnancy and neonatal outcome, including gestational age at delivery, mode of delivery, indication for cesarean delivery, complications, neonatal birthweight, Apgar scores, and neonatal intensive care unit (NICU) admission, were collected. The date of data cutoff for outcomes was March 24, 2020. The degree of severity of COVID-19 pneumonia (severe vs nonsevere) was defined by the Infectious Diseases Society of America/American Thoracic Society guidelines for community-acquired pneumonia.
Two study investigators (J.Y. and J.J.) independently reviewed the data collection forms to verify data accuracy. Major disagreement between them was resolved by consultation with a third investigator (H.Y.).
Sample collection
Amniotic fluid samples from patients with COVID-19 pneumonia were obtained through direct needle syringe aspiration at the time of cesarean delivery. Cord blood and neonatal pharyngeal swab samples were collected immediately after delivery in the operating or delivery room. Evidence of vertical transmission was evaluated by testing for the presence of SARS-CoV-2 in these clinical samples. In addition, vaginal secretion samples were collected from the lower third of the vagina on admission, and breast milk samples were collected at first lactation in Zhongnan Hospital of Wuhan University and Renmin Hospital of Wuhan University. All samples were processed at the State Key Laboratory of Virology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, and Laboratory Medicine Center of Renmin Hospital of Wuhan University for further testing. Sample collection, processing, and laboratory testing complied with WHO guidance. All samples, as described above, were tested for SARS-CoV-2 using qRT-PCR with the Chinese Center for Disease Control and Prevention–recommended kit.
Study outcomes
The primary endpoint was admission to ICU, use of mechanical ventilation, or death. Secondary endpoints were the rates of spontaneous abortion, preterm delivery, cesarean delivery, and neonatal COVID-19.
Statistical analysis
Continuous variables were expressed as means (standard deviations [SDs]) or medians (interquartile ranges [IQRs]) or simple ranges, as appropriate. Categorical variables were summarized as numbers and percentages. The results were presented in the total study population and according to the methods of diagnosis for COVID-19 pneumonia. The statistical software SPSS for Windows version 23 (SPSS, IL) was used for data analyses.
Results
Clinical characteristics
The characteristics and outcomes of the study population of 116 cases, including 65 cases of laboratory-confirmed and 51 cases of clinically diagnosed COVID-19 pneumonia, are presented in Table 1 . The mean age was 30.8 (range 24–41) years, and median gestational age on admission was 38 +0 (IQR 36 +0 –39 +1 ) weeks. In 59.5% (69/116) of cases, women reported a history of relevant environmental exposure, and 32.8% (38/116) had contact with infected persons. The most common symptoms at presentation were fever in 50.9% (59/116), cough in 28.4% (33/116), and fatigue in 12.9% (15/116) of cases. In 23.3% (27/116) of cases, there were no signs or symptoms of the disease, 77.8% (21/27) of which were clinically diagnosed with COVID-19 pneumonia. All these 21 cases underwent investigations because of marked epidemiologic history.
| Clinical characteristics | All patients (n=116) | Laboratory confirmed (n=65) | Clinically diagnosed (n=51) |
|---|---|---|---|
| Age, y | |||
| Mean±SD | 30.8±3.8 | 30.3±3.7 | 31.3±4.0 |
| Range | 24.0–41.0 | 24.0–40.0 | 24.0–41.0 |
| Gestational age on admission, wk | |||
| Median (IQR) | 38.0 (36.0, 39.1) | 36.7 (33.8, 38.4) | 39.0 (38.0, 39.4) |
| Range | 5–41 +2 | 5–41 +2 | 30–41 |
| <13 +6 , n (%) | 4 (3.4) | 4 (6.2) | 0 |
| 14–27 +6 , n (%) | 6 (5.2) | 6 (9.2) | 0 |
| 28–36 +6 , n (%) | 30 (25.9) | 24 (36.9) | 6 (11.8) |
| ≥37, n (%) | 76 (65.5) | 31 (47.7) | 45 (88.2) |
| Parity | |||
| Nulliparous, n (%) | 64 (55.2) | 37 (56.9) | 27 (52.9) |
| Multiparous, n (%) | 52 (44.8) | 28 (43.1) | 24 (47.1) |
| Epidemiologic history | 107 (92.3) | 65 (100) | 42 (82.3) |
| Relevant environmental exposure, n (%) | 69 (59.5) | 39 (60.0) | 30 (58.8) |
| Contact with infected person, n (%) | 38 (32.8) | 26 (40.0) | 12 (23.5) |
| Symptoms | |||
| Fever a , n (%) | 59 (50.9) | 45(69.2) | 14 (27.5) |
| Cough, n (%) | 33 (28.4) | 28 (43.1) | 5 (9.8) |
| Fatigue, n (%) | 15 (12.9) | 13 (20.0) | 2 (3.9) |
| Shortness of breath, n (%) | 9 (7.8) | 8 (12.3) | 1 (2.0) |
| Sore throat, n (%) | 10 (8.6) | 10 (15.4) | 0 |
| Myalgia, n (%) | 6 (5.2) | 5 (7.7) | 1 (2.0) |
| Dyspnea, n (%) | 3 (2.6) | 3 (4.6) | 0 |
| Diarrhea, n (%) | 1 (0.9) | 1 (1.5) | 0 |
| No symptoms, n (%) | 27 (23.3) | 6 (9.2) | 21 (41.2) |
| Pregnancy complications | |||
| Gestational diabetes mellitus | 9 (7.8) | 3 (4.6) | 6 (11.8) |
| Hypertensive disorders | 5 (4.3) | 2 (3.1) | 3 (5.9) |
| Preeclampsia | 4 (3.4) | 1 (1.5) | 3 (5.9) |
| Disease severity | |||
| Severe | 8 (6.9) | 6 (9.2) | 2 (3.9) |
| Nonsevere | 108 (93.1) | 59 (90.8) | 49 (96.1) |
| Treatment | |||
| Antibiotic therapy | 109 (94.0) | 58 (89.2) | 51 (100) |
| Antiviral therapy | 63 (54.3) | 48 (73.8) | 15 (29.4) |
| Use of corticosteroid | 37 (31.9) | 26 (40.0) | 11 (21.6) |
| ICU admission | 8 (6.9) | 6 (9.2) | 2 (3.9) |
| Noninvasive ventilation | 6 (5.2) | 6 (9.2) | 0 |
| Invasive mechanical ventilation | 2 (1.7) | 2 (3.1) | 0 |
| ECMO | 1 (0.9) | 1 (1.5) | 0 |
| Plasmapheresis | 1 (0.9) | 0 | 1 (2.0) |
| Clinical outcomes | |||
| Remained in hospital | 40 (34.5) | 24 (36.9) | 16 (31.4) |
| Discharged | 76 (65.5) | 41 (63.1) | 35 (68.6) |
| Died | 0 | 0 | 0 |
a Including postpartum fever cases. Data are expressed as n (%). Outcomes were followed up until March 24, 2020.
Of note, there were 9 patients (7.8%, 9/116) with gestational diabetes and 5 (4.3%, 5/116) with hypertensive disorders, including 4 (3.4%, 4/116) with preeclampsia, and these pregnancy complications were unrelated to COVID-19 pneumonia. There were 8 patients (6.9%, 8/116) with severe pneumonia, all required ICU admission, 1 of whom (0.9%, 1/116) required plasmapheresis, 6 (5.2%, 6/116) received noninvasive ventilation, 2 (1.7%, 2/116) received invasive mechanical ventilation, and 1 (0.9%, 1/116) received extracorporeal membrane oxygenation. Clinical details of severe pneumonia cases are presented in the Supplemental Table . A total of 76 (65.5%, 76/116) cases had been discharged. There were no cases of maternal death.
On admission, lymphocytopenia was present in 44.0% (51/116) of the patients and leukopenia was present in 24.1% (28/116) of patients, according to pregnancy-specific reference ranges. Elevated levels of C-reactive protein were found in 44% of the patients. Patients with severe disease had more prominent laboratory abnormalities (including lymphocytopenia and leukopenia) than those with nonsevere disease. In cases that underwent chest CT scans at the time of admission, 96.3% (104/108) revealed abnormal results. Of note, all cases of clinically diagnosed COVID-19 pneumonia exhibited abnormal chest CT findings ( Table 2 ).
| Laboratory and radiologic findings | All patients (n=116) | Laboratory confirmed (n=65) | Clinically diagnosed (n=51) |
|---|---|---|---|
| Leucocytes (∗10 9 /L; reference range a ) | |||
| Median (IQR) | 7.9 (5.9, 10.6) | 7.5 (5.2, 9.8) | 8.9 (6.7, 11.0) |
| Decreased, n (%) | 28 (24.1) | 20 (30.8) | 8 (15.7) |
| Normal, n (%) | 85 (73.3) | 42 (64.6) | 43 (84.3) |
| Increased, n (%) | 3 (2.6) | 3 (4.6) | 0 |
| Lymphocytes (∗10 9 /L; reference range, 1.1–3.2) | |||
| Median (IQR) | 1.2 (0.9, 1.6) | 1.0 (0.8, 1.6) | 1.3 (1.1, 1.6) |
| Decreased, n (%) | 51 (44.0) | 38 (58.5) | 13 (25.5) |
| Normal, n (%) | 64 (55.1) | 26 (40.0) | 38 (74.5) |
| Increased, n (%) | 1 (0.9) | 1 (1.5) | 0 |
| C-reactive protein concentration (mg/L; reference range, 0–10) | |||
| Median (IQR) | 9.3 (3.3, 28.0) | 16.6 (5.3, 37.9) | 5.9 (2.6, 21.6) |
| Increased, n (%) | 51 (44.0) | 32 (49.2) | 19 (37.3) |
| Normal, n (%) | 53 (45.7) | 24 (36.9) | 29 (56.9) |
| CT chest findings (n=108) | |||
| Patchy shadowing or ground-glass opacity, n (%) | 104 (96.3) | 53 (93.0) | 51 (100%) |
| Negative finding, n (%) | 4 (3.7) | 4 (7.0) | 0 |
a Reference range in pregnancy: first trimester, 5.7–13.6 ∗10 9 /L; second trimester, 5.6–14.8 ∗10 9 /L; and third trimester, 5.9–16.9 ∗10 9 /L (from Williams Obstetrics 25th Edition 27 ). Data are expressed as n (%). Increased means over the upper limit of the reference range and decreased means below the lower limit of the reference range.
Pregnancy outcomes
Of the 116 pregnant women with COVID-19 pneumonia, 8 cases presented before 24 weeks’ gestation. One case (12.5%, 1/8) was complicated with a missed spontaneous abortion at 5 +2 weeks at presentation with fever and fatigue. In the remaining 7 ongoing cases, 4 had reached 20 weeks, and morphology scan revealed normal anatomy and fetal growth. Ten cases presented between 24 and 33 +6 weeks, of which 7 cases are ongoing, 1 delivered at term, and 2 cases (20%, 2/10) had iatrogenic preterm delivery. One had a cesarean delivery at 28 +1 weeks on the same day of admission for severe pneumonia; 1 had a cesarean delivery at 31 +6 weeks on the same day of admission for twin pregnancy. Of the 22 cases presented between 34 and 36 +6 weeks, 19 delivered preterm, 2 delivered at term, and 1 case remained undelivered. There were 27.3% (6/22) women who had preterm premature rupture of membranes (PPROM), 2 cases (33.3%, 2/6) resulted in vaginal delivery; 4 cases (66.7%, 4/6) required cesarean delivery, with 3 cases indicated for symptomatic COVID-19 pneumonia and 1 because of history of previous cesarean delivery. There are 16 ongoing pregnancies, with 1 patient with gestational diabetes mellitus and the other 15 patients with no fetal or maternal complications reported as of March 24, 2020.
A total of 99 pregnant women, including 1 with twin pregnancy, delivered their babies during hospitalization, of whom 85.9% (85/99) underwent cesarean delivery and 14.1% (14/99) had a vaginal delivery ( Table 3 ). Cesarean delivery was indicated for COVID-19 pneumonia in 38.8% (33/85), previous cesarean delivery in 18.8% (16/85), fetal distress in 10.6% (9/85), and failure to progress in 5.9% (5/85) ( Table 3 ). The rates of preterm delivery before 34 weeks and 37 weeks were 2.0% (2/99) and 21.2% (21/99), respectively ( Table 3 ). Among the 21 preterm deliveries, 28.6% (6/21) had PPROM, 2 of which resulted in vaginal deliveries. There were no cases with spontaneous onset of labor. The rate of spontaneous preterm birth before 37 weeks was therefore 6.1% (6/99). No cases of spontaneous preterm delivery before 34 weeks were reported.
| Outcome | All deliveries (n=99) | Laboratory confirmed (n=50) | Clinically diagnosed (n=49) |
|---|---|---|---|
| Mode of delivery | |||
| Cesarean delivery, n (%) | 85 (85.9) | 44 (88.0) | 41 (83.7) |
| Vaginal delivery, n (%) | 14 (14.1) | 6 (12.0) | 8 (16.3) |
| Indication of cesarean delivery a | |||
| COVID-19 pneumonia, n (%) | 33 (38.8) | 19 (43.2) | 14 (34.1) |
| Previous cesarean delivery, n (%) | 16 (18.8) | 8 (18.2) | 8 (19.5) |
| Fetal distress, n (%) | 9 (10.6) | 7 (15.9) | 2 (4.9) |
| Failure to progress, n (%) | 5 (5.9) | 3 (6.8) | 2 (4.9) |
| Preeclampsia, n (%) | 4 (4.7) | 1 (2.3) | 3 (7.3) |
| Abnormal fetal growth, n (%) | 2 (2.4) | 0 | 2 (4.9) |
| Placenta previa, n (%) | 3 (3.5) | 0 | 3 (7.3) |
| Others, n (%) | 13 (15.3) | 6 (13.6) | 7 (17.1) |
| Onset of symptoms to delivery, d | |||
| Median (IQR) | 2.5 (1.0, 6.7) | 4.0 (1.0, 7.0) | 4.0 (0.5, 8.5) |
| Range | 0–38.0 | 0–38.0 | 0–22.0 |
| Gestational age at delivery | |||
| Median (IQR) | 38.4 (37.3, 39.4) | 38.0 (36.6, 39.2) | 39.0 (38.1, 39.4) |
| Range | 28.1–41.3 | 28.1–41.3 | 31.9–41.0 |
| <34 wk, n (%) | 2 (2.0) | 1 (2.0) | 1 (2.0) |
| 34–36 +6 wk, n (%) | 19 (19.2) | 15 (30.0) | 4 (8.2) |
| ≥37 wk, n (%) | 78 (78.8) | 34 (68.0) | 44 (89.8) |
| Preterm delivery before 34 wk, n (%) | 2 (2.0) | 1 (2.0) | 1 (2.0) |
| Spontaneous labor-PPROM | 0 | 0 | 0 |
| Preterm delivery before 37 wk, n (%) | 21 (21.2) | 16 (32.0) | 5 (10.2) |
| Spontaneous labor-PPROM | 6 (6.1) | 3 (6.1) | 3 (6.1) |
| Clinical outcome of neonates (n=100) b | |||
| Neonatal birthweight (g) | 3108±526 | 3087±504 | 3130±553 |
| Apgar 1-min, median (IQR) | 9 (8, 9) | 9 (8, 9) | 9 (9, 9) |
| Apgar 5-min, median (IQR) | 10 (9, 10) | 10 (9, 10) | 10 (10, 10) |
| Severe neonatal asphyxia, n (%) | 1 (1.0) | 1 (2.0) | 0 |
| Transferred to NICU, n (%) | 47 (47.0) | 17 (34.0) | 30 (60.0) |
| Remained in hospital, n (%) | 23 (23.0) | 13 (26.0) | 10 (20.0) |
| Discharged, n (%) | 76 (76.0) | 36 (72.0) | 40 (80.0) |
| Neonatal death, n (%) | 1 (1.0) | 1 (2.0) | 0 |
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